Multimodality imaging of ss-cells in animal models of T1DM and T2DM Abstract: The expression of imaging reporter genes in ss-cells has provided powerful tools for studying ss-cell development, diabetes and islet transplantation. We have generated transgenic mice (MIP-TF mice) that express a fusion protein of three different imaging reporters (EGFP- luciferase-thymidine kinase) in their ss-cells. This should enable the longitudinal noninvasive imaging of ss-cells in the same animal by CCD and microPET, and the identification of ss-cells at the cellular level by fluorescent microscopy. The goals of this proposal are designed to provide proof-of-principle that multimodality imaging of ss-cells can augment and expedite a broad range of type 1 and type 2 diabetes mellitus (T1DM and T2DM) studies. Specific Aims: 1). Do trifusion reporter signals provide a noninvasive biomarker of the gain of ss-cell mass in MIP-TF C57Bl6 mice fed a high fat diet, a widely used model of T2DM? 2). Can the ss-cells of MIP-TF C57BL6 mice be noninvasively imaged by microPET? 3). Do trifusion reporter signals correlate with the loss of ss-cell mass during the spontaneous development of T1DM in MIP-TF NOD mice? Together, this project will;1) enable the first microPET imaging of ss-cells in mice, which would expedite the translation of ss-cell imaging to clinical applications and;2) enable researchers to collect ss-cell imaging data by one modality and use this data to predict the results of other imaging modalities, and equate the results with ss-cell mass. We anticipate that the data and transgenic mice that this project will generate will help other scientists to advance T1DM and T2DM research on a broad number of fronts, including studies of ss-cell development, ss-cell mass during diabetes pathogenesis, stem cell differentiation into ss-cells, transdifferentiation, and islet survival after transplantation. PUBLIC HEALTH RELEVANCE Laypersons abstract: We have generated transgenic mice that express a protein in their ss-cells that should enable researchers to image ss-cells in living animals by three different imaging techniques, allowing researchers to monitor ss-cells in living animals and at the cellular level in tissue sections. It is expected that this animal model will expedite a broad range of diabetes research, including studies of ss-cell development, embryonic and adult stem cell differentiation into ss-cells, transdifferentiation, islet transplantation and islet imaging.